The advantages of sustained release formulations are well known in the pharmaceutical field. These include the ability of the given pharmaceutical preparation to maintain a desired therapeutic effect over a comparatively longer period of time, reduced side effects, etc. Moreover, for drugs having a short elimination half-life, less frequent administration and better patient compliance may be obtained with sustained release preparations as compared to the conventional dosage forms.
Development of a sustained release dosage form demands considerable understanding of the gastrointestinal physiology. There is a natural pH gradient down the gut from acidity of stomach to weakly acidic duodenum to the neutral environment of the small intestine. Also there are possible fluctuations in pH arising from dietary changes.
Another important factor is the transit time of the dosage form. Transit time determines the time period for which a dosage form remains in a particular segment of gastrointestinal tract. The transit time usually depends on the dosage form itself, gastric motility, presence of food etc.
Combination of pH and transit time determines the environment experienced by a dosage form for example transit time of a tablet in stomach under fasting condition may range from 0.5-2 hours. This means that a tablet will experience a pH of less than 2 for a period of 0.5-2 hours.
These factors, i.e. transit time and pH are highly variable for different individuals, same individual at different time periods, and therefore these factors become very crucial for release of active agent particularly from a modified release dosage form. It is always desirable for optimal use of the drug product that the product be independent of these variabilities and avoid the associated problems of bioavailability variation.
Prior art discloses many patents on controlled and sustained release delivery systems, some of which also describes formulations giving pH independent release profiles.
U.S. Pat. Nos. 4,927,640, 4,957,745 and 5,246,714 describe controlled release beads comprising a compact inert core, which is insoluble and a polymeric membrane. The inner core is made of silicon dioxide, glass or plastic resin particles while the polymeric membrane covering the pharmaceutically active compound may be ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methyl phthalate, cellulose acetate phthalate, Eudragit RL or Eudragit RS. Although such systems provide pH independent release profile, the process of manufacturing is very complicated and involves use of organic solvents, which is not desirable. The complicated manufacturing steps make the process cumbersome, time consuming and expensive.
U.S. Pat. No. 4,792,452 discloses controlled release pharmaceutical compositions, which provide pH-independent release for a basic drug. The formulations include a pH-dependent polymer, which is a salt of alginic acid, a pH-independent hydrocolloid gelling agent and a binder and the formulation is free of calcium ion and carbon dioxide-producing material. The salt of the alginic acid is preferably sodium alginate or potassium alginate. This patent is applicable only for basic drugs and cannot be applied to acidic or neutral drugs. Moreover the system is dependent on highly variable physiological conditions for conversion of sodium alginate to alginic acid and back to sodium alginate. This may result in inter patient as well as intra patient variabilities leading to suboptimal product performance.
WO02058676 describes a composition exhibiting a pH independent release profile of an active having pH dependent solubility. The formulation comprises a combination of pH independent and a pH dependent polymer which increases dissolution rate of active at a pH greater than 5.5.
WO0045793 discloses extended release formulations of acidic drugs, which have reduced dependence of release rate on pH. The dosage form includes a neutral water swellable hydrophilic polymer and acid soluble polymer, which is water swellable above pH 5.0.
U.S. Pat. No. 6,346,268 discloses a controlled release formulation comprising a pH dependent gelling polymer, an enteric polymer and a pH independent gelling polymer.
The last three patents, mentioned above, describe formulations of drugs having pH dependent solubilities, which tend to make the release of drug also pH dependent. These patents therefore employ a pH dependent polymer to increase the dissolution of the drug in a medium, where its solubility is low, so as to achieve constant drug release. These patents also disclose use of a pH independent, swelling release-retarding polymer, which control the release of the active agent. These systems however may not be useful for drug molecules having high aqueous solubility, which is independent of the pH of the medium. Use of these systems may result in undesirably high initial burst release of the drug.
Thus there is a need to develop a sustained release dosage form, which performs reproducibly with low variability. Such dosage forms would have two essential features—(1) pH independent drug release for a considerable period of time and, (2) absence of significant swelling of the dosage form leading to predictable gastrointestinal transit profile.
It was surprisingly found that both these desired features were achieved by the dosage form of the present invention by employing a combination of a non-swelling pH dependent release retardant and a non-swelling pH independent release retardant. It is generally known in the art that use of pH dependent release retardants alone results in a release profile of the active ingredient, which is dependent on the pH of the environment. However optimal selection of type and concentration of release retardants by the present inventors has resulted in a sustained release dosage form, which releases drug at a rate that is independent of the surrounding milieu for a considerable period of time.